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Polyglandular Deficiency Syndromes

(Autoimmune Polyglandular Syndromes; Polyendocrine Deficiency Syndromes)

By

Jennifer M. Barker

, MD, Children's Hospital Colorado, Division of Pediatric Endocrinology

Last full review/revision Apr 2021
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Topic Resources

Polyglandular deficiency syndromes (PDS) are characterized by sequential or simultaneous deficiencies in the function of several endocrine glands that have a common cause. Etiology is most often autoimmune. Categorization depends on the combination of deficiencies, which fall within 1 of 3 types. Diagnosis requires measurement of hormone levels and autoantibodies against affected endocrine glands. Treatment includes replacement of missing or deficient hormones and sometimes immunosuppressants.

Etiology

The etiology is most often autoimmune. Risk factors for development of autoimmunity include

  • Genetic factors

  • Environmental triggers

  • Drugs

Genetic factors include the AIRE gene mutation, which is causative of type 1, and certain human leukocyte antigen (HLA) subtypes, which are important in the development of types 2 and 3.

Environmental triggers include viral infections, dietary factors, and other as yet unknown exposures.

Immune check point inhibitors Immunotherapy and Targeting Inhibitors of Immune Responses A number of immunologic interventions, both passive and active, can be directed against tumor cells. (See also Immunotherapeutics.) In passive cellular immunotherapy, specific effector cells... read more , which are used to treat some types of cancer and are associated with autoimmune endocrine disease, including hypophysitis, thyroid disease, primary adrenal insufficiency, and type 1 diabetes mellitus, are a trigger.

Pathophysiology

The underlying autoimmune reaction involves autoantibodies against endocrine tissues, cell-mediated autoimmunity Cellular Components of the Immune System The immune system consists of cellular components and molecular components that work together to destroy antigens. (See also Overview of the Immune System.) Although some antigens (Ags) can... read more , or both and leads to inflammation, lymphocytic infiltration, and partial or complete gland destruction. More than one endocrine gland is involved, although clinical manifestations are not always simultaneous. The autoimmune reaction and associated immune system dysfunction can also damage nonendocrine tissues.

Classification

Type 1 polyglandular deficiency

Type 1 polyglandular deficiency, also known as autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), usually begins in childhood. It is caused by mutations in the AIRE gene and is inherited in an autosomal recessive pattern. It is defined by the presence of ≥ 2 of the following:

Candidiasis is usually the initial clinical manifestation, most often occurring in patients < 5 years of age. Hypoparathyroidism occurs next, usually in patients < 10 years. Lastly, adrenal insufficiency occurs in patients < 15 years. Accompanying endocrine and nonendocrine disorders (see table Characteristics of Polyglandular Deficiency Syndromes Characteristics of Polyglandular Deficiency Syndromes Polyglandular deficiency syndromes (PDS) are characterized by sequential or simultaneous deficiencies in the function of several endocrine glands that have a common cause. Etiology is most often... read more ) continue to appear at least until patients are about age 40.

Type 2 polyglandular deficiency

Type 2 polyglandular deficiency, also known as Schmidt syndrome, usually occurs in adults; peak incidence is age 30. It occurs 3 times more often in women. It is associated with certain human leukocyte antigen (HLA) genotypes and exhibits polygenic inheritance. It typically manifests with the following:

Type 3 polyglandular deficiency

Classification reference

Symptoms and Signs

The clinical appearance of patients with polyglandular deficiency syndromes is the sum of the individual endocrine deficiencies and associated nonendocrine disorders; their symptoms and signs are discussed elsewhere in THE MANUAL. The deficiencies do not always appear at the same time and may require a period of years to manifest; in such cases they do not follow a particular sequence.

Diagnosis

  • Measurement of hormone levels

  • Sometimes autoantibody titers

Diagnosis of polyglandular deficiency syndromes is suggested clinically and confirmed by detecting deficient hormone levels. Other causes of multiple endocrine deficiencies include hypothalamic-pituitary dysfunction and coincidental endocrine dysfunction due to separate causes (eg, tuberculous hypoadrenalism and nonautoimmune hypothyroidism in the same patient).

Type 1 polyglandular deficiency is associated with autoantibodies against type 1 interferons, and presence of these antibodies suggests the diagnosis, which can be confirmed by mutational analysis of the AIRE gene. Detecting autoantibodies to each affected glandular tissue can help differentiate polyglandular deficiency syndromes from the other causes, and elevated levels of pituitary tropic hormones (eg, thyroid-stimulating hormone) suggest the hypothalamic-pituitary axis is intact (although some patients with type 2 polyglandular deficiency syndrome have hypothalamic-pituitary insufficiency).

Because decades may pass before the appearance of all manifestations, lifelong follow-up is prudent; unrecognized hypoparathyroidism or adrenal insufficiency can be life threatening.

Relatives should be made aware of the diagnosis and screened when appropriate. A trial following relatives of patients with type 1 diabetes for development of autoimmunity found antibodies associated with type 1 diabetes, celiac disease, and/or thyroid disease in 21.5% of subjects (1 Diagnosis reference Polyglandular deficiency syndromes (PDS) are characterized by sequential or simultaneous deficiencies in the function of several endocrine glands that have a common cause. Etiology is most often... read more ).

Diagnosis reference

  • 1. Winkler C, Jolink M, Knopff A, et al: Age, HLA, and sex define a marked risk of organ-specific autoimmunity in first-degree relatives of patients with type 1 diabetes. Diabetes Care 42:1684–1691, 2019. doi: 10.2337/dc19-0315

Treatment

  • Hormone replacement

Treatment of the various individual glandular deficiencies is discussed elsewhere in THE MANUAL; the treatment of multiple deficiencies can be more complex than treatment of an isolated endocrine deficiency. For example, treatment of hypothyroidism with thyroid hormone replacement can precipitate an adrenal crisis in patients with undiagnosed adrenal insufficiency.

Clinical trials of interventions to slow the autoimmune process in type 1 diabetes have shown some promise in delaying the complete destruction of insulin-producing beta-cells. Treatments that have been evaluated include immunotherapy and umbilical cord blood transplantation. Treatments are still experimental (1–3 Treatment references Polyglandular deficiency syndromes (PDS) are characterized by sequential or simultaneous deficiencies in the function of several endocrine glands that have a common cause. Etiology is most often... read more ).

Treatment references

  • 1. Cai J, Wu Z, Xu X, et al: Umbilical cord mesenchymal stromal cell with autologous bone marrow cell transplantation in established type 1 diabetes: A pilot randomized controlled open-label clinical study to assess safety and impact on insulin secretion. Diabetes Care 39:149–157, 2016.

  • 2. Haller MJ, Gitelman SE, Gottlieb PA, et al: Anti-thymocyte globulin/G-CSF treatment preserves β cell function in patients with established type 1 diabetes. J Clin Invest 125(1):448–455, 2015.

  • 3. Kroger CJ, Clark M, Ke Q, and Tisch RM: Therapies to suppress β cell autoimmunity in type 1 diabetes. Front Immunol 9:1891, 2018. doi: 10.3389/fimmu.2018.01891

Key Points

  • Polyglandular deficiency syndromes involve deficiencies in the function of several endocrine glands, which may occur simultaneously or sequentially.

  • Nonendocrine organs also may be affected.

  • Most cases are autoimmune; triggers are often unknown but may involve viruses, dietary substances, or drugs.

  • Polyglandular deficiency syndromes are distinguished by the glands affected.

  • Treatment involves replacement of deficient hormones.

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